Biology subjects

Mollenhauer, B.

Publications and source records attributed to Mollenhauer, B..

11 recordsLinked to original sources

bioRxiv2026

Herpes simplex virus infection promotes ALS pathology through ICP0-mediated PML body disruption

Transactive response DNA binding protein 43 kDa (TDP-43) pathology, is a central molecular hallmark of amyotrophic lateral sclerosis (ALS). However, the underlying triggers are incompletely understood. Here, we show that infection with herpes simplex virus (HSV) induces molecular hallmarks of ALS in various in vitro and in vivo models and is associated with an increased risk of ALS in human population data. German healthcare provider data (n = 238,440) and herpesvirus serology of an ALS patient and control cohort (n = 1,100) showed that HSV infection elevated the ALS risk by 210% and odds by [~]65%, respectively. On a molecular level, HSV infection promoted TDP-43 pathology in neuronal cell models, human iPSC-derived motoneurons and cerebral organoids, mice, and human tissue sections. This effect was triggered by HSV-1 or 2, but not by several other related herpesviruses. Mechanistically, the infected cell protein 0 (ICP0) of HSV-1/2 drives TDP-43 pathology by disturbance of promyelocytic leukemia nuclear bodies (PML-NBs), thereby abrogating TDP-43 SUMO2/3ylation. Taken together, we reveal a previously unrecognized association between HSV infection and ALS and clarify the underlying molecular mechanism that drives TDP-43 pathology. Our data may guide future studies into therapeutic and prophylactic interventions against ALS.

neuroscience↗

bioRxiv2024

Human gut microbiome gene co-expression network reveals a loss in taxonomic and functional diversity in Parkinson's disease

Alterations of gut microbiome structure have been observed in a panoply of human diseases including neurodegeneration. However, the ecological and functional deficits of microbiome dysbiosis have yet to be understood. Here, using integrated multi-omics (metagenomics and metatranscriptomics), we resolve microbiome gene co-expression networks in individuals with Parkinsons disease (PD) and healthy individuals. We uncover network modules with high closeness and degree centrality that represent core ecological functions, and identify key features lost in PD. More specifically, we observe a significant depletion in specific functions including secondary bile acid biosynthesis and flagellar assembly (FA) in PD. Strikingly, most hub genes, particularly those involved in bacterial microcompartments (BMCs) and FA, are predominantly found in healthy individuals. Blautia and Anaerobutyricum genera are the main contributors to these functions, showing significantly lower expression of BMC genes in PD. Additionally, we identify a strong correlation between the expression of BMC and FA genes, but also an apparent dysregulation in cross feeding between commensals in PD. Importantly, gene expression in PD was tied to reduced diversity in expressed genes, whereas in healthy individuals, higher expression levels were linked to higher diversity. Our findings reveal disruptions in key gut metabolic functions at both functional and taxonomic levels, potentially driving disease progression. Notably, we identify crucial microbiome-wide ecological features that should be restored in future gut microbiome rewilding efforts.

microbiology↗

bioRxiv2024

Integrated multi-omics highlights alterations of gut microbiome functions in prodromal and idiopathic Parkinson's disease

Parkinsons disease (PD) is associated with gut microbiome shifts, but the functional consequences remain unclear. Here, we use an integrated multi-omics approach to compare the gut microbiomes of individuals with PD and prodromal PD as well as healthy individuals. After analyzing each omics, meta-metabolomic was selected to inform the analysis as it represents the most discriminatory and robust ome. We identified 11 metabolites that were differentially abundant between the groups, amongst which {beta}-glutamate was increased in PD and prodromal PD, and correlated with the transcriptional activities of Methanobrevibacter smithii and Clostridium spp. We identified decreases in transcripts, but not in gene abundances, related to glutamate metabolism, bile acids, chemotaxis and flagellar assembly in PD, particularly in keystone genera such as Roseburia, Agathobacter and Blautia. Our findings, integrated into the Expobiome map, reveal multifactorial microbiome alterations which converge with PD pathways. Our study highlights the importance of investigating the gut microbiomes functional dimensions to better resolve microbiome-host interactions in health and disease.

systems biology↗

bioRxiv2024

The epitranscriptomic m6A RNA modification modulates synaptic function in ageing and in a mouse model of synucleinopathy

N6-methyladenosine (m6A) is the most abundant and conserved transcriptional modification in eukaryotic RNA, regulating RNA fate. While the functions of m6A in the development of the mammalian brain have been extensively studied, its roles in synaptic plasticity, cognitive decline, motor function, or other brain circuits remain underexplored. To date, the role of this modification in Parkinsons disease (PD) and other synucleinopathies has been largely unknown. Here, we investigated the m6A epitranscriptome in a mouse model of synucleinopathy. We performed m6A RNA immunoprecipitation sequencing (meRIP-seq) to obtain the m6A epitranscriptome of the midbrain in young (3 mo) and aged (15 mo) A30P-aSyn transgenic mice (aSyn Tg) and C57BL6 control wild type (Wt) mice. We observed hypermethylation of synaptic genes in 3 mo aSyn Tg mice compared to age-matched Wt mice. This methylation was reduced during ageing, with synaptic genes becoming increasingly hypomethylated. Using immunofluorescence imaging alongside biochemical analysis, we further investigated the expression of m6A regulatory enzymes -- writer, N6-Adenosine-Methyltransferase Complex Catalytic Subunit (METTL3); reader, YTH N6-methyladenosine RNA-binding protein (YTHDF1); and eraser, fat mass and obesity-associated protein (FTO) -- in the cortex, striatum, hippocampus, and cerebellum of Wt and aSyn Tg mice, as well as in primary cortical neuronal cultures. We observed that the levels of METTL3, YTHDF1 and FTO were similar between Wt and aSyn Tg mice. Interestingly, the writer protein METTL3 was found in both the nucleus and in the post-synaptic compartment in neuronal cultures. Our findings suggest that alterations in the regulation of m6A RNA methylation may be associated with neurodegeneration and ageing and that this level of epitranscriptomic regulation plays a significant role at the synapse.

neuroscience↗

bioRxiv2022

Expansion microscopy at one nanometer resolution

Fluorescence imaging is one of the most versatile and widely-used tools in biology1. Although techniques to overcome the diffraction barrier were introduced more than two decades ago, and the nominal attainable resolution kept improving2, 3, fluorescence microscopy still fails to image the morphology of single proteins or small molecular complexes, either purified or in a cellular context4, 5. Here we report a solution to this problem, in the form of one-step nanoscale expansion (ONE) microscopy. We combined the 10-fold axial expansion of the specimen (1000-fold by volume) with a fluorescence fluctuation analysis6, 7 to enable the description of cultured cells, tissues, viral particles, molecular complexes and single proteins. At the cellular level, using immunostaining, our technology revealed detailed nanoscale arrangements of synaptic proteins, including a quasi-regular organisation of PSD95 clusters. At the single molecule level, upon main chain fluorescent labelling, we could visualise the shape of individual membrane and soluble proteins. Moreover, conformational changes undergone by the [~]17 kDa protein calmodulin upon Ca2+ binding were readily observable. We also imaged and classified molecular aggregates in cerebrospinal fluid samples from Parkinsons Disease (PD) patients, which represents a promising new development towards improved PD diagnosis. ONE microscopy is compatible with conventional microscopes and can be performed with the software we provide here as a free, open-source package. This technology bridges the gap between high-resolution structural biology techniques and light microscopy, and provides a new avenue for discoveries in biology and medicine.

biophysics↗

bioRxiv2020

Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system

The causative agent of the current pandemic and coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. Understanding how SARS-CoV-2 enters and spreads within human organs is crucial for developing strategies to prevent viral dissemination. For many viruses, tissue tropism is determined by the availability of virus receptors on the surface of host cells2. Both SARS-CoV and SARS-CoV-2 use angiotensin-converting enzyme 2 (ACE2) as a host receptor, yet, their tropisms differ3-5. Here, we found that the cellular receptor neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, which was inhibited by a monoclonal blocking antibody against the extracellular b1b2 domain of NRP1. NRP1 is abundantly expressed in the respiratory and olfactory epithelium, with highest expression in endothelial cells and in the epithelial cells facing the nasal cavity. Neuropathological analysis of human COVID-19 autopsies revealed SARS-CoV-2 infected NRP1-positive cells in the olfactory epithelium and bulb. In the olfactory bulb infection was detected particularly within NRP1-positive endothelial cells of small capillaries and medium-sized vessels. Studies in mice demonstrated, after intranasal application, NRP1-mediated transport of virus-sized particles into the central nervous system. Thus, NRP1 could explain the enhanced tropism and spreading of SARS-CoV-2.

microbiology↗

bioRxiv2020

Deep sncRNA-seq of the PPMI cohort to study Parkinson's disease progression

Coding and non-coding RNAs have diagnostic and prognostic importance in Parkinsons diseases (PD). We studied circulating small non-coding RNAs (sncRNAs) in 7, 003 samples from two longitudinal PD cohorts (Parkinsons Progression Marker Initiative (PPMI) and Luxembourg Parkinsons Study (NCER-PD)) and modelled their influence on the transcriptome. First, we sequenced sncRNAs in 5, 450 blood samples of 1, 614 individuals in PPMI. The majority of 323 billion reads (59 million reads per sample) mapped to miRNAs. Other covered RNA classes include piRNAs, rRNAs, snoRNAs, tRNAs, scaRNAs, and snRNAs. De-regulated miRNAs were associated with the disease and disease progression and occur in two distinct waves in the third and seventh decade of live. Originating mostly from a characteristic set of immune cells they resemble a systemic inflammation response and mitochondrial dysfunction, two hallmarks of PD. By profiling 1, 553 samples from 1, 024 individuals in the NCER-PD cohort using an independent technology, we validate relevant findings from the sequencing study. Finally, network analysis of sncRNAs and transcriptome sequencing of the original cohort identified regulatory modules emerging in progressing PD patients.

neuroscience↗

bioRxiv2019

A nanobody-based fluorescent reporter reveals human α-synuclein in the cell cytosol

Aggregation and spreading of -Synuclein (Syn) are hallmarks of several neurodegenerative diseases, thus monitoring human Syn (hSyn) in animal models or cell cultures is vital for the field. However, the detection of native hSyn in such systems is challenging. We found that the nanobody NbSyn87, previously-described to bind hSyn, also shows cross-reactivity for the proteasomal subunit Rpn10. As such, when the NbSyn87 is expressed in the absence of hSyn, it is continuously degraded by the proteasome, while it is stabilized when it binds to hSyn. Here, we exploited this feature to design a new Fluorescent Reporter for hSyn (FluoReSyn) by coupling NbSyn87 to fluorescent proteins, which results in fluorescence signal fluctuations depending on the presence and amounts of intracellular hSyn. We characterized this biosensor in cells and tissues, and finally, revealed the presence of transmittable Syn in human cerebrospinal fluid demonstrating the potential of FluoReSyn for clinical research and diagnostics.

neuroscience↗

bioRxiv2019

Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in non-human primates

AO_SCPLOWBSTRACTC_SCPLOWDopaminergic neuronal cell death, associated with intracellular -synuclein (-syn)-rich protein aggregates (termed Lewy bodies), is a well-established characteristic of Parkinsons disease. Much evidence, accumulated from multiple experimental models has suggested that -syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct -syn pathogenic structures derived from PD patients. Unexpectedly, our results show that, in non-human primates, a small amount of singular -syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD as multiple causes can induce similar outcome regarding dopaminergic neurodegeneration.

neuroscience↗

bioRxiv2019

Cross-Sectional and Longitudinal Validation of Serum Neurofilament Light Chain (NfL) as a Biomarker of Parkinson’s Disease Progression

ObjectiveTo assess neurofilament light chain (NfL), as a biomarker for Parkinsons disease (PD). MethodsWe quantified NfL in (1) longitudinal CSF samples from PD, other cognate/neurodegenerative disorders (OND), and healthy controls (HC); (2) a cross-sectional cohort with paired CSF and serum samples from participants with PD, OND, and HC, and (3) a large longitudinal validation cohort with serum samples from PD, OND, HC, prodromal conditions, and mutation carriers. ResultsIn the longitudinal discovery cohort (1) NfL in CSF was highest in OND and higher in PD vs. HC across all visits (p<0.05) but did not change longitudinally. In the cross-sectional cohort (2) paired CSF and serum NfL samples were highly correlated (Spearmans rank [Formula]; p<10^-6). In the large validation cohort (3) mean baseline serum NfL was higher in PD (13{+/-}7.2pg/ml) vs. HC (12{+/-}6.7pg/ml; p=0.0336) and was highest in OND (18{+/-}7pg/ml; p=0.0351). Serum NfL increased longitudinally in PD vs. HC (p<0.01). Longitudinal motor scores were positively longitudinally associated with NfL, whereas some cognitive scores showed a negative longitudinal association with NfL. ConclusionsNfL levels in serum samples are increased in PD vs. HC, increase significantly over time, and correlate with clinical measures of PD severity. Although the specificity of NfL in PD is low and more specific biomarkers are needed, serum NfL is the first blood-based biomarker candidate that could support disease stratification (PD vs. OND), track clinical progression, and possibly assess responsiveness to neuroprotective treatments. NfL as a biomarker of response to neuroprotective interventions remains to be determined. Funding sources for studyPPMI is sponsored by the Michael J. Fox Foundation for Parkinsons Research (MJFF) and is co-funded by MJFF, Abbvie, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, Eli Lilly & Co., F. Hoffman-La Roche, Ltd., GE Healthcare, Genentech, GlaxoSmithKline, Lundbeck, Merck, MesoScale, Piramal, Pfizer and UCB. The funders had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, in the preparation, review, or approval of the manuscript or in the decision to submit the manuscript for publication. Financial Disclosure/Conflict of Interest concerning the research related to the manuscriptBrit Mollenhauer, Douglas Galasko, Tatiana Foroud, Lana M. Chahine, Christopher S. Coffey, Andrew B. Singleton, Tanya Simuni, Daniel Weintraub, John Seibyl, Arthur W. Toga, and Caroline M. Tanner received funding from The Michael J. Fox Foundation for Parkinsons Research. Mohammed Dakna, Tzu-Ying Liu, Henrik Zetterberg, Sebastian Schade, Roland G. Gera, Wenting Wang, Feng Gao, Niels Kruse, Mark Frasier, Jesse M. Cedarbaum, Samantha J. Hutten, Claudia Trenkwalder, and Danielle Graham report no disclosures.

neuroscience↗

bioRxiv2019

Fine-mapping of SNCA in REM sleep behavior disorder and overt synucleinopathies

ObjectiveREM-sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants.\n\nMethodsFull sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n=1,076), Parkinsons disease (PD, n=1,013), and dementia with Lewy bodies (DLB, n=415), and in control subjects (n=6,155). A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (cases n=1,782, controls n=131,250). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis.\n\nResultsA 5-region SNCA variant (rs10005233) was associated with iRBD (OR=1.43, p=1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5 risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3 of SNCA (OR=1.32, p=4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR=5.74, p=2E-06). The known top PD-associated variant (3 variant rs356182) had an opposite direction of effect in iRBD compared to PD.\n\nInterpretationThere is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3 of SNCA. Several 5 SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies, and may suggest a cognitive component to this region.

genetics↗